This project is driven by the hypothesis that current in vivo models for evaluating cancer therapies are too non-predictive of the human condition for efficient use. This may become a major impediment to the translation of new potential drugs into effective therapies for patients. The project proposes to determine if transgenic pigs may serve as a novel and more human-like model for cancer. Although pigs have been used extensively in biomedical research, to date, there is no reported transgenic swine model for cancer. Like humans, pigs can live for decades and have a very low rate of spontaneous cancer. This is in contrast to common rodent-based cancer models, where life span is limited to a few years and the spontaneous development of cancer is quite high. We now know that 5-6 to six genetic defects are required to convert a normal pig cell into a tumor cell. This is the same as in humans. However, mouse cells can be transformed into tumor cells by as little as two genetic lesions. These simple yet profound genetic observations point to pigs as a far superior model system for the human condition. We propose to use state of the art technology to generate transgenic pigs that can be induced to lose the expression of three major tumor suppressors simultaneously in the breast. These alterations will be coupled with an up-regulation of a growth hormone receptor. These genetic defects are often found in breast cancer and particularly in Triple Negative (TN) breast cancer. TN breast cancer is an especially aggressive and difficult to treat form of breast cancer with a high morbidity rate. We will include a far red fluorescent protein in the system which will allow non-invasive imaging of the status of the induced breast cells. The project will involve the collaboration of laboratories with extensive experience in the molecular and cellular biology of human breast cancer and laboratories with world renown in the production and husbandry of transgenic pigs. Animals will be tested to determine if these lesions are sufficient to provoke breast cancer and whether any such cancers have the characteristics of TN breast cancer. We will also use the population to test the effectiveness of cancer chemopreventative agents, and whether the pigs respond to front line therapy for TN breast cancer in a similar manner to humans. PUBLIC HEALTH RELEVANCE: This project will establish a novel model system for evaluating new therapeutic approaches to cancer. The system should be much more predictive for the human condition, thus enhancing the ability to identify and characterize effective novel therapeutics. It may also establish a unique model for the study of cancer preventative strategies that cannot be realistically modeled at present. The model is targeted towards breast cancer as over 40 thousand women are expected to die in the United states each year from this disease due to lack of sufficiently effective therapies.